Pharmacological modulation of epigenetic changes in AML

AML 表观遗传变化的药理学调节

• 批准号: 8505766
• 负责人: Monica L Guzman
• 金额: $ 32.29万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8505766
• 关键词: Aberrant DNA Methylation; Acute Myelocytic Leukemia; Adult; Adult Acute Myeloblastic Leukemia; Aftercare; Attention; Blast Cell; Bortezomib; Cancer and Leukemia Group B; Chemotherapy-Oncologic Procedure; Child; Childhood; Childhood Acute Myeloid Leukemia; Clinic; Clinical; Clinical Trials; Complement; DNA; Data; Decitabine; Disease; Disease remission; Dose; Drug Kinetics; Elderly; Epigenetic Process; FDA approved; Failure; Funding; Gene Expression; Gene Silencing; Genes; Genetic; Goals; Grant; Histone Deacetylase Inhibitor; Hypermethylation; Indium; Laboratory Study; Leadership; Mediating; Methylation; MicroRNAs; Molecular; Mutation; Myelogenous; Ohio; Outcome; Paper; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phenotype; Phosphotransferases; Process; Proteasome Inhibitor; Proteins; Publications; Publishing; Recruitment Activity; Refractory; Regimen; Relapse; Reporting; Research; Resistance; Role; Safety; Series; Testing; Therapeutic; Toxic effect; Translational Research; Universities; Up-Regulation; age group; arm; base; bone marrow hyperplasia; chemotherapy; clinical efficacy; design; gene function; genome wide methylation; genome-wide; high risk; improved; insight; leukemic stem cell; leukemogenesis; member; molecular marker; novel; novel strategies; novel therapeutic intervention; prognostic; public health relevance; resistance mechanism; response; stem cell biology; success; therapeutic target; tripolyphosphate; two-arm study; young adult

DESCRIPTION (provided by applicant): The majority of children and adults with acute myeloid leukemia (AML) die of their disease and therefore, novel therapeutic approaches beyond "one-fits-all" chemotherapy regimens are required. Epigenetic gene silencing has been reported to be involved in the deregulation of hematopoietic cell proliferation, differentiation and survival in AML and contributes to leukemogenesis. We have been focusing on pharmacological targeting of aberrant DNA methylation that mediates epigenetic gene silencing in AML. Decitabine (DAC) is an azanucleoside with hypomethylating activity. In the last funding cycle of this R01 grant, we have brought to the clinic and demonstrated the excellent activity of a regimen of low-dose DAC (20 mg/m2/day x10 day) and the feasibility of the combination of DAC with the proteasome inhibitor bortezomib. We have shown that untreated older AML patients can achieve a complete remission rate of approximately 50% with these DAC-based regimens. In addition we have made several discoveries with regard to: (a) potential molecular predictors of clinical response to DAC (miR-29b and DNMT3A mutations); (b) novel mechanisms of myeloid leukemogenesis involving epigenetics, microRNAs and kinases, and (c) novel compounds that enhance the pharmacologic activity of DAC through up regulation of microRNAs (i.e., AR42, a histone deacetylase inhibitor designed and developed at the OSU). These novel clinical, molecular and pharmacologic findings now need to be validated and their mechanisms further understood in order to move forth the epigenetic-targeting approaches in AML. To achieve this goal, we also need to define the molecular basis for treatment resistance to epigenetic-targeting therapies, not only at the level of bulk AML blasts, but also in leukemia stem cells (LSC). Thus, we have now designed two new clinical trials and a series of novel pharmacodynamic studies that will unveil the interplay among DNA hypermethylation, microRNAs, and LSC through the following Specific Aims: (1)To conduct a larger Phase II clinical trial (CALGB 11002) in untreated older (>60 years) AML to compare the clinical activity of decitabine (DAC) vs. decitabine (DAC) + bortezomib and identify the predictive and pharmacodynamic (PD) factors that determine therapeutic differences between these two regimens; (2) To conduct a Phase I clinical trial (OSU 11130) of the HDAC inhibitor AR42 followed by DAC (AR42->DAC) to define toxicity, clinical response and pharmacokinetic (PK) and pharmacodynamic (PD) factors that determine the clinical outcomes in adult and pediatric patients with AML; (3) To determine the impact of epigenetic- targeting therapies on the function and survival of leukemic stem cells (LSCs) and how this contributes to disease response or resistance in AML patients to DAC-based regimens.

描述（由申请人提供）：大多数患有急性骨髓性白血病（AML）死于其疾病的儿童和成年人，因此，除了“一件能力”的化学疗法方案之外，还需要采取新的治疗方法。据报道，表观遗传基因沉默与AML中造血细胞增殖，分化和存活有关，并有助于白血病发生。我们一直专注于异常DNA甲基化的药理靶向，该甲基化介导AML中的表观遗传基因沉默。去替滨（DAC）是一种具有降甲基活性的偶氮核苷。在此R01赠款的最后一个资金周期中，我们带到了诊所，并证明了低剂量DAC（20 mg/m2/day x10天）的良好活性以及DAC与蛋白酶体抑制剂bortezomib的可行性。我们已经表明，未经治疗的老年AML患者可以通过这些基于DAC的方案实现约50％的完全缓解率。此外，我们已经对：（a）对DAC的临床反应的潜在分子预测指标（miR-29b和dnmt3a突变）； （b）涉及表观遗传学，microRNA和激酶的髓样白血病发生的新型机制，以及（c）新颖的化合物，通过增加MicroRNA的调节（即AR42，一种组蛋白脱乙酰基酶抑制剂AR42）在OSU上设计和开发了DAC的药理活性。现在需要对这些新型的临床，分子和药理发现结果进行验证，并进一步理解其机制，以便在AML中采用表观遗传靶向方法。为了实现这一目标，我们还需要定义对表观遗传靶向疗法的耐药性的分子基础，不仅在散装AML爆炸水平上，而且在白血病干细胞（LSC）中。因此，我们现在已经设计了两项新的临床试验和一系列新型的药效学研究，这些研究将通过以下具体目的揭示DNA高甲基化，microRNA和LSC之间的相互作用：（1）在未经培训的AML（> 60岁）AML（> 60岁）AML（> 60年）中进行较大的II阶段临床试验（CALGB 11002）进行了decital（DAC） + decitabine（DAC）（DAC）（DAC）DAC（DSC）。硼替佐米并确定确定这两种方案之间治疗差异的预测性和药效学因素（PD）因子； （2）进行HDAC抑制剂AR42的I期临床试验（OSU 11130），然后进行DAC（AR42-> DAC），以定义毒性，临床反应和药代动力学（PK）和药物学（PD）因素（PD）因素，这些因素确定了成人和儿童aml具有AML的临床临床效果； （3）确定表观遗传靶向疗法对白血病干细胞功能和存活（LSC）的影响，以及这如何促进AML患者对基于DAC的治疗方案的疾病反应或抗性。